Hallows Kenneth R, Abebe Kaleab Z, Li Hui, Saitta Biagio, Althouse Andrew D, Bae Kyongtae T, Lalama Christina M, Miskulin Dana C, Perrone Ronald D, Seliger Stephen L, Watnick Terry J
Department of Medicine, Division of Nephrology and Hypertension, University of Southern California Keck School of Medicine, Los Angeles, California, USA.
Department of Medicine, Division of General Internal Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Kidney Int Rep. 2022 Dec 5;8(3):467-477. doi: 10.1016/j.ekir.2022.11.019. eCollection 2023 Mar.
Dysregulated cellular metabolism contributes to autosomal dominant polycystic kidney disease (ADPKD) pathogenesis. The Trial of Administration of Metformin in Polycystic Kidney Disease (TAME-PKD) tested the effects of metformin treatment over 2 years in adult ADPKD patients with mild-moderate disease severity. Metformin was found to be safe and tolerable with an insignificant trend toward reduced estimated glomerular filtration rate (eGFR) decline compared to placebo. Here we tested whether targeted urinary metabolic biomarkers measured in TAME-PKD participants correlated with disease progression, severity, and metformin treatment in cross-sectional and longitudinal analyses.
Concentrations of total protein, targeted metabolites (lactate, pyruvate, and succinate), and glycolytic enzymes (pyruvate kinase-M2, lactate dehydrogenase-A, and pyruvate dehydrogenase kinase-1) were measured and normalized by creatinine or osmolality in urine specimens and compared with height-adjusted total kidney volume (htTKV) and eGFR at the different study timepoints.
In cross-sectional analyses utilizing placebo group data, urinary succinate normalized by creatinine negatively correlated with ln (htTKV), whereas protein excretion strongly positively correlated with ln (htTKV), and negatively correlated with eGFR. Significant time-varying negative associations occurred with eGFR and the lactate/pyruvate ratio and with urine protein normalized by osmolality, indicating correlations of these biomarkers with disease progression. In secondary analyses, urinary pyruvate normalized by osmolality was preserved in metformin-treated participants but declined in placebo over the 2-year study period with a significant between-arm difference, suggesting time-dependent urinary pyruvate changes may serve as a discriminator for metformin treatment effects in this study population.
Proteinuria with enhanced glycolytic and reduced oxidative metabolic markers generally correlated with disease severity and risk of progression in the TAME-PKD study population.
细胞代谢失调在常染色体显性多囊肾病（ADPKD）发病机制中起作用。多囊肾病二甲双胍给药试验（TAME-PKD）对成年中轻度ADPKD患者进行了为期2年的二甲双胍治疗效果测试。结果发现，与安慰剂相比，二甲双胍安全且耐受性良好，估计肾小球滤过率（eGFR）下降趋势不显著。在此，我们通过横断面和纵向分析测试了TAME-PKD参与者中测量的靶向尿代谢生物标志物是否与疾病进展、严重程度和二甲双胍治疗相关。
测量尿标本中总蛋白、靶向代谢物（乳酸、丙酮酸和琥珀酸）和糖酵解酶（丙酮酸激酶-M2、乳酸脱氢酶-A和丙酮酸脱氢酶激酶-1）的浓度，并通过肌酐或渗透压进行标准化，然后与不同研究时间点的身高校正总肾体积（htTKV）和eGFR进行比较。
在利用安慰剂组数据的横断面分析中，经肌酐标准化的尿琥珀酸与ln(htTKV)呈负相关，而蛋白排泄与ln(htTKV)呈强正相关，与eGFR呈负相关。eGFR与乳酸/丙酮酸比值以及经渗透压标准化的尿蛋白之间存在显著的随时间变化的负相关，表明这些生物标志物与疾病进展相关。在二次分析中，经渗透压标准化的尿丙酮酸在二甲双胍治疗的参与者中保持稳定，但在安慰剂组中在2年研究期间下降，组间差异显著，这表明随时间变化的尿丙酮酸变化可能是该研究人群中二甲双胍治疗效果的一个判别指标。
在TAME-PKD研究人群中，蛋白尿伴糖酵解增强和氧化代谢标志物降低通常与疾病严重程度和进展风险相关。
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